A computed tomography scan shows a
bladder tumor (arrows) before sequential
multidrug chemotherapy. The patient had
no cancer remaining at cystectomy and
remained cancer-free 9 years later..

Cisplatin-based
chemotherapy is the standard neoadjuvant treatment for high-risk,
surgically resectable, invasive urothelial cancer. But some patients
are not good candidates for this chemotherapy owing to certain disease
characteristics or comorbidities.

These patients may benefit from an alternative regimen of sequential
neoadjuvant chemotherapy with ifosfamide, doxorubicin, and gemcitabine
(IAG) followed by gemcitabine, low-dose cisplatin, and ifosfamide
(CGI), according to the results of a recent clinical trial.

Such sequential chemotherapy is not typically prescribed in the
neoadjuvant setting, according to Arlene Siefker-Radtke, M.D., an
associate professor in the Department of Genitourinary Medical Oncology
at The University of Texas MD Anderson Cancer Center and the trial’s
principal investigator. In designing the study, however, Dr.
Siefker-Radtke and her colleagues hypothesized that a sequential
approach that included a strong alkylating agent up front followed by a
reduced cisplatin dose would minimize the toxic effects of cisplatin.

The patients were scheduled to receive three cycles of IAG followed by
four cycles of CGI. The IAG regimen, which was composed of ifosfamide
with mesna on days 1–4, doxorubicin on day 3, and gemcitabine on days 2
and 4, was given with growth factor support in an inpatient setting and
repeated every 3 weeks. The CGI regimen, which was composed of
gemcitabine, ifosfamide, and cisplatin with mannitol on the same day
every 2 weeks, was given with growth factor support as needed in an
inpatient or outpatient clinic. Patients underwent cystoscopy after 6
weeks of treatment, and IAG was continued in patients whose tumors
responded to the therapy but discontinued early in patients whose
tumors did not respond. Patients whose tumors had not responded were
switched to six cycles of CGI.

The trial’s primary endpoint was tumor downstaging to pathologic (p)
T1N0 disease or lower at the time of cystectomy; such downstaging
occurred in 30 of the 60 patients who had primary bladder tumors and 3
of the 5 patients who had primary tumors of the renal pelvis.
Sixty-five percent of patients who completed three cycles of IAG before
receiving CGI had their disease downstaged to pT1N0 or lower.
Twenty-six percent of patients who switched to CGI early because of
lack of response or toxicity had their disease downstaged to pT1N0.

Only two of the patients whose disease did not respond to IAG achieved
pT0 disease after CGI. Dr. Siefker-Radtke said this might indicate that
the lower doses of cisplatin and ifosfamide in the CGI regimen were not
sufficient to kill IAG-resistant tumor cells.

Patients who had pT1N0 disease or lower, pT2–T3aN0 disease, or pT3b
disease or higher or lymph node-positive disease had 5-year overall
survival rates of 87%, 67%, and 27%, respectively. Together, the
patients had a 63% 5-year overall survival rate and a 68% 5-year
disease-specific survival rate. These results were similar to what has
been seen historically with cisplatin-based chemotherapy, suggesting
that the sequential regimen may be a suitable alternative for some
patients who are not able to receive full-dose cisplatin.

One patient died of pneumonia during the first cycle of IAG. Three
patients experienced grade 4 toxicities; grade 3 toxicities were more
common but not overwhelming. No patient developed peripheral neuropathy
as a result of chemotherapy. Eleven patients required dose reductions
of IAG, and 10 patients required dose reductions of CGI. The report of
the study was published this February in Cancer.

Dr. Siefker-Radtke said that although the regimen is not a good fit for
all patients—especially those with poor renal function—it may be an
attractive alternative for patients who are not good candidates for the
standard regimen, such as those who have preexisting peripheral
neuropathy or hearing loss that may worsen with cisplatin treatment.

For more
information, contact Dr. Arlene Siefker-Radtke at 713-792-2830.